Biochemical basis for D,L,-beta-hydroxybutyrate-induced teratogenesis.
Previous investigations have demonstrated that a potential mechanism for D,L,-beta-hydroxybutyrate (BOHB)-induced teratogenesis in neurulating mouse embryos (5-6 somite stage) after 24 hours of exposure in vitro is mediated by an inhibition of the pentose phosphate pathway (PPP) (Hunter, et al. '87). Employing conceptuses of an earlier stage (2-3 somite stage), the biochemistry of BOHB-induced abnormalities was examined further by exposing embryos to 32 mM BOHB for 24 hour and comparing results with controls with respect to the rate of metabolism via the PPP, de novo pyrimidine biosynthesis (PB), and BOHB utilization. Moreover, the capability of these BOHB-exposed embryos to recover from such an insult was also assessed by transferring them to fresh control medium and allowing them to grow for an additional 36 hours. Both controls and BOHB-exposed embryos showed a progressive increase in rate of BOHB utilization between days 9 and 11.5 of gestation in vitro. Exposure to ketone body produced a 100% rate of neural tube defects and a 25.2% decrease in total embryonic protein content. In contrast to results obtained at the 5-6 somite stage, no inhibition of the PPP in whole conceptuses, embryos, or visceral yolk sacs was observed in the group exposed to BOHB at the 2-3 somite stage. Furthermore, a 7.5 mM D-ribose supplement, an intermediate in the PPP, was unable to rescue the younger embryos from BOHB-induced abnormalities and growth retardation. On the other hand, BOHB produced a 34.3% decrease in pyrimidine biosynthesis in the 2-3 somite embryos, but not in the visceral yolk sac. In addition, embryos recovered biochemically after being transferred to control medium, demonstrating a 25.5% overshoot in pyrimidine biosynthesis. Therefore, the mechanism of BOHB-induced teratogenesis appears to differ depending on the stage of embryonic development at the time of initial exposure.
Shum
L
L
Department of Cell Biology and Anatomy, University of North Carolina, Chapel Hill 27599-7090.
Sadler
T W
TW
D020155:3-Hydroxybutyric Acid; D000818:Animals; D046508:Culture Techniques; D006885:Hydroxybutyrates / Q000633:toxicity*; D051379:Mice; D008815:Mice, Inbred Strains; D009132:Muscles / Q000196:embryology; D009436:Neural Tube Defects / Q000139:chemically induced; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D011743:Pyrimidines / Q000096:biosynthesis*; D013723:Teratogens
D006885:Hydroxybutyrates; D011743:Pyrimidines; D013723:Teratogens; D020155:3-Hydroxybutyric Acid